Azilsartan medoxomil i.e. (5-methyl-2-oxo-1,3-dioxol-4-yl)methyl 2-ethoxy-1-([2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-1H-benzimidazole-7-carboxylate (1) and salts thereof has the uses such as a strong and long lasting angiotensin II antagonistic activity and hypotensive action, and an insulin sensitizing activity, and which is useful as an agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases (cardiac hypertrophy, cardiac failure, cardiac infarction and the like), nephritis, stroke and the like and metabolic diseases such as diabetes and the like (U.S. Pat. No. 7,157,584). Azilsartan medoxomil is the prodrug of 2-ethoxy-1-([2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl)-1H-benzimidazole-7-carboxylic acid.

Methods of preparing benzimidazole derivative useful as an angiotensin II receptor antagonist such as azilsartan medoxomil and salt thereof such as monopotassium salt (IA) are described in U.S. Pat. No. 5,243,054 (herein after referred as U.S. '054 patent).
The U.S. '054 patent describes several synthetic routes for preparing azilsartan. According to one synthetic process, azilsartan is prepared by the synthetic route as depicted below in Scheme 1. According to Scheme 1 cyanobiphenyl derivative compound of formula (2) reacts with hydroxylamine hydrochloride in a conventional organic solvent to give hydroxyamidino derivative of formula (3), which on further cyclization in presence of a base and chloroformic acid ester yielded the 1,2,4-oxadiazol derivative compound of formula (4). 1,2,4-oxadiazol derivative compound of formula (4) was further hydrolyzed in presence of a base to obtain azilsartan (5). Also, J. Med. Chem. Vol. 39, No. 26, 5230-5237 (1996) follows the same reaction sequence with minor changes in reagents such as use of triethylamine as base during the conversion of cyano group to hydroxyamidino derivative of formula (3); use of 2-ethylhexylchloroformate instead of ethylchloroformate as cyclizing agent with compound of formula (3).

According to another method disclosed in U.S. '054 for the preparation of azilsartan (Scheme 2), ethoxycarboimidoyl biphenyl benzimidazole derivative of compound of formula (6) reacts with ethylchloroformate in presence of 2,6-dimethylpyridine as base gives N-methoxycarbonyl ethoxycarboimidoylbiphenyl benzimidazole derivative of compound of formula (7). The resulting N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole compound of formula (7) can be converted to 1,2,4-oxadiazol derivative compound of formula (4) by either of the two ways: (i) by treating the compound of formula (7) with hydroxylamine hydrochloride in presence of sodium methoxide; (ii) by reacting compound of formula (7) with methyl chloroformate in presence of 2,4,6-trimethylpyridine to obtain a residue, which on further addition to a mixture of hydroxylamine hydrochloride and sodium methoxide under reflux yielded compound of formula (4). 1,2,4-Oxadiazol derivative compound of formula (4) thus obtained is further hydrolyzed in presence of a base to obtain azilsartan (5).

According to one another method for the preparation of azilsartan disclosed in U.S. '054 (Scheme 3), cyanobiphenyl aminobenzoate derivative compound of formula (8) reacts with hydroxylamine hydrochloride in presence of triethylamine subsequently followed by addition of ethyl chlorocarbonate to give ethoxycarbonyloxycarbamimidoyl derivative of formula (9). The resulting ethoxycarbonyloxycarbamimidoyl derivative of formula (9) can be converted to 1,2,4-oxadiazol derivative compound of formula (4) by either of the two ways: (i) by treating the compound of formula (9) with potassium carbonate; (ii) by reacting compound of formula (9) with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). 1,2,4-Oxadiazol derivative compound of formula (4) thus obtained is further hydrolyzed in presence of a base to obtain azilsartan (5).

It is known that synthetic compounds can contain extraneous compounds or impurities resulting from their synthesis or degradation. The impurities can be unreacted starting materials, by-products of the reaction, products of side reactions, or degradation products. Generally, impurities in an active pharmaceutical ingredient (API) may arise from degradation of the API itself, or during the preparation of the API. Impurities in azilsartan medoxomil or any active pharmaceutical ingredient (API) are undesirable and might be harmful, as they would be carried over to pharmaceutical compositions, used for human consumption.
According to U.S. '054 patent (Scheme 1), the preparation of 1,2,4-oxadiazol derivative compound of formula (4) by reacting cyano biphenyl derivative compound of formula (2) with hydroxylamine hydrochloride, as depicted in Scheme 1, yields about 10-12% of the desethyl impurity of formula (10), which accounts for the yield loss and impair the quality of the product.
According to U.S. '054 patent (Scheme 1), cyanobiphenyl derivative compound of formula (2) reacts with hydroxylamine hydrochloride in presence of sodium methoxide as base to give hydroxyamidino derivative of formula (3). Also, J. Med. Chem. Vol. 39, No. 26, 5230-5237 (1996) follows the same reaction sequence with minor changes in reagents such as use of triethylamine as base during the conversion of cyano group to hydroxyamidino derivative of formula (3). When we repeat these processes for the preparation of hydroxyamidino derivative of formula (3), we obtain amide impurity of compound of formula (12) in approximately about 50% along with desired product, which accounts for the yield loss and impair the quality of the product. Such formation of impurity would demand the exhaustive purification.
Moreover, other processes as depicted in Schemes 2 and 3 disclosed in U.S. '054 involve multistep for the preparation of azilsartan and in turn azilsartan medoxomil. Also, these processes give low yield, thus making them to be economically expensive on commercial scale.

U.S. Pat. No. 7,157,584 discloses process for preparation of azilsartan medoxomil which process comprises reacting 1-[[2′-(4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]-2-ethoxy-1H-benzimidazole-7-carboxylic acid with 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one in presence of dimethylacetamide, p-toluoyl sulfonylchloride, 4-dimethylaminopyridine and potassium carbonate.
Conversion of azilsartan (5) into azilsartan medoxomil (1) in high yield is important on higher scale, which demands improved process of preparation of medoxomil component such as 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (11), though there exist the literature such as Synthetic communications, 22(9), 1277-1282 (1992) for the preparation of 4-hydroxymethyl-5-methyl-1,3-dioxol-2-one (11).
Regulatory authorities worldwide require drug manufactures to isolate, identify and characterize the impurities in their products. Furthermore, it is required to control the levels of these impurities in the final drug substance obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels and within the limits, even if structural determination is not possible.
Accordingly, there remains a need for highly pure azilsartan medoxomil substantially free of impurities, as well as purification processes for obtaining them on commercially economical scale.